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Distinctive pattern of sequence polymorphism in the NS3 protein of hepatitis C virus type 1b reflects conflicting evolutionary pressures.

ABSTRACT: Analysis of complete polyprotein-encoding sequences of hepatitis C virus genotype 1b (HCV-1b) showed evidence not only of past purifying selection but also of abundant slightly deleterious non-synonymous variants subject to ongoing purifying selection. The NS3 protein (with protease and NTPase/helicase activity) revealed less evidence of purifying selection acting on the cytotoxic T cells (CTL) epitopes than did the other proteins, whereas outside the CTL epitopes NS3 was more conserved than the other proteins. Moreover, NS3 showed a high incidence of forward-and-backward or parallel non-synonymous changes in CTL epitopes, as measured by the consistency index across the phylogeny of HCV-1b genomes computed at non-singleton non-synonymous polymorphic sites. This result implies that certain non-synonymous mutations have recurred frequently throughout the phylogeny in the codons encoding the epitopes in NS3. This pattern is most easily explained by the frequent re-occurrence of the same set of escape mutations in CTL epitopes of NS3, which are selectively favoured within hosts expressing the presenting class I major histocompatibility complex molecule, but are subject to purifying selection at the population level. The fact that this pattern is most strikingly observed in the case of NS3 suggests that the evolutionary conflict between immune escape and functional constraint on the protein is more acute in the case of NS3 than any of the other proteins of HCV-1b.

SUBMITTER: Irausquin SJ

PROVIDER: S-EPMC2577380 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

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Distinctive pattern of sequence polymorphism in the NS3 protein of hepatitis C virus type 1b reflects conflicting evolutionary pressures.

Irausquin Stephanie Jiménez SJ Hughes Austin L AL

The Journal of general virology 20080801 Pt 8

Analysis of complete polyprotein-encoding sequences of hepatitis C virus genotype 1b (HCV-1b) showed evidence not only of past purifying selection but also of abundant slightly deleterious non-synonymous variants subject to ongoing purifying selection. The NS3 protein (with protease and NTPase/helicase activity) revealed less evidence of purifying selection acting on the cytotoxic T cells (CTL) epitopes than did the other proteins, whereas outside the CTL epitopes NS3 was more conserved than the ...[more]

PMID: 18632963

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Project description:The genetic architecture of many phenotypic traits is such that genes often contribute to multiple traits, and mutations in these genes can therefore affect multiple phenotypes. These pleiotropic interactions often manifest as tradeoffs between traits where improvement in one property entails a cost in another. The life cycles of many pathogens include periods of growth within a host punctuated with transmission events, such as passage through a digestive tract or a passive stage of exposure in the environment. Populations exposed to such fluctuating selective pressures are expected to acquire mutations showing tradeoffs between reproduction within and survival outside of a host. We selected for individual mutations under fluctuating selective pressures for a ssDNA microvirid bacteriophage by alternating selection for increased growth rate with selection on biophysical properties of the phage capsid in high-temperature or low-pH conditions. Surprisingly, none of the seven unique mutations identified showed a pleiotropic cost; they all improved both growth rate and pH or temperature stability, suggesting that single mutations even in a simple genetic system can simultaneously improve two distinct traits. Selection on growth rate alone revealed tradeoffs, but some mutations still benefited both traits. Tradeoffs were therefore prevalent when selection acted on a single trait, but payoffs resulted when multiple traits were selected for simultaneously. We employed a molecular-dynamics simulation method to determine the mechanisms underlying beneficial effects for three heat-shock mutations. All three mutations significantly enhanced the affinities of protein-protein interfacial bindings, thereby improving capsid stability. The ancestral residues at the mutation sites did not contribute to protein-protein interfacial binding, indicating that these sites acquired a new function. Computational models, such as those used here, may be used in future work not only as predictive tools for mutational effects on protein stability but, ultimately, for evolution.

Dataset Information

Distinctive pattern of sequence polymorphism in the NS3 protein of hepatitis C virus type 1b reflects conflicting evolutionary pressures.

Publications

Distinctive pattern of sequence polymorphism in the NS3 protein of hepatitis C virus type 1b reflects conflicting evolutionary pressures.

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